Packaging and delivery of pharmaceuticals and drugs

ABSTRACT

A blister pack for use with inhalation therapy inhalers comprises an elongate bottom element having an overlying top element defining a plurality of spaced top crowned areas containing powder or liquid medications or drugs.

The present application is a continuation of U.S. patent applicationSer. No. 09/888,837, filed Jun. 25, 2001, now U.S. Pat. No. 7,080,644,which claims priority from U.S. Provisional Application Ser. No.60/214,578, filed Jun. 28, 2000.

FIELD OF THE INVENTION

The present invention relates generally to the field of metering,packaging and delivery of pharmaceuticals and drugs. Particular utilityfor the present invention is found in the area of facilitating meteringand packaging of medications and drugs for inhalation therapy and willbe described in connection with such utilities, although other utilitiesare contemplated, including liquid medication applications.

DISCUSSION OF THE PRIOR ART

Certain diseases of the respiratory tract are known to respond totreatment by the direct application of therapeutic agents. As theseagents are most readily available in dry powdered form, theirapplication is most conveniently accomplished by inhaling the powderedmaterial through the nose or mouth. This powdered form results in thebetter utilization of the medication in that the drug is depositedexactly at the site desired and where its action may be required; hence,very minute doses of the drug are often equally as efficacious as largerdoses administered by other means, with a consequent marked reduction inthe incidence of undesired side effects and medication cost.Alternatively, the drug in this form may be used for treatment ofdiseases other than those of the respiratory system. When the drug isdeposited on the very large surface areas of the lungs, it may be veryrapidly absorbed into the blood stream; hence, this method ofapplication may take the place of administration by injection, tablet,or other conventional means.

It is the opinion of the pharmaceutical industry that thebioavailability of the drug is optimum when the drug particles deliveredto the respiratory tract are between 1 to 5 microns in size. When thedrug particles need to be in this size range the dry powder deliverysystem needs to address a number of issues:

(1) Small size particles develop an electrostatic charge on themselvesduring manufacturing and storage. This causes the particles toagglomerate or aggregate, resulting in clusters of particles which havean effective size greater than 5 microns. The probability of these largeclusters making it to the deep lungs then decreases. This in turnresults in a lower percentage of the packaged drug being available tothe patient for absorption.

(2) The amount of active drug that needs to be delivered to the patientmay be of the order of 10s of micrograms. For example, albuterol, in thecase of a drug used in asthma, this is usually 25 to 50 micrograms.Current manufacturing equipment can effectively deliver aliquots ofdrugs in milligram dose range with acceptable accuracy. So the standardpractice is to mix the active drug with a filler or bulking agent suchas lactose. This additive also makes the drug “easy to flow”. Thisfiller is also called a carrier since the drug particles also stick tothese particles through electrostatic or chemical bonds. These carrierparticles are very much larger than the drug particles in size. Theability of the dry powder inhaler to separate drug from the carrier isan important performance parameter in the effectiveness of the design.

(3) Active drug particles with sizes greater than 5 microns will bedeposited either in the mouth or throat. This introduces another levelof uncertainty since the bioavailability and absorption of the drug inthese locations is different from the lungs. Dry powder inhalers need tominimize the drug deposited in these locations to reduce the uncertaintyassociated with the bioavailability of the drug.

Prior art dry powder inhalers (DPIs) usually have a means forintroducing the drug (active drug plus carrier) into a high velocity airstream. The high velocity airstream is used as the primary mechanism forbreaking up the cluster of micronized particles or separating the drugparticles from the carrier. Several inhalation devices useful fordispensing this powder form of medication are known in the prior art.For example, in U.S. Pat. Nos. 3,507,277; 3,518,992; 3,635,219;3,795,244; and 3,807,400, inhalation devices are disclosed having meansfor piercing or removing the top of a capsule containing a powderedmedication, which upon inhalation is drawn out of the pierced or toppedcapsule and into the user's mouth. Several of these patents disclosepropeller means, which upon inhalation aid in dispensing the powder outof the capsule, so that it is not necessary to rely solely on theinhaled air to suction powder from the capsule. For example, in U.S.Pat. No. 2,517,482, a device is disclosed having a powder containingcapsule placed in a lower chamber before inhalation, where it is piercedby manual depression of a piercing pin by the user. After piercing,inhalation is begun and the capsule is drawn into an upper chamber ofthe device where it moves about in all directions to cause a dispensingof powder through the pierced hole and into the inhaled air stream. U.S.Pat. No. 3,831,606 discloses an inhalation device having multiplepiercing pins, propeller means, and a self-contained power source foroperating the propeller means via external manual manipulation, so thatupon inhalation the propeller means aids in dispensing the powder intothe stream of inhaled air. See also U.S. Pat. No. 5,458,135.

These prior art devices present several problems and possess severaldisadvantages which are remedied by the inhalation devices of thepresent invention. For instance, these prior art devices require thatthe user exert considerable effort in inhalation to effect dispensing orwithdrawal of powder from a pierced capsule into the inhaled air stream.With these prior art devices, suction of powder through the piercedholes in the capsule caused by inhalation generally does not withdrawall or even most of the powder out of the capsule, thus causing a wasteof the medication. Also, such prior art devices may result inuncontrolled amounts or clumps of powdered material being inhaled intothe user's mouth, rather than a constant inhalation of controlledamounts of finely dispersed powder.

The above description of the prior art is taken largely from U.S. Pat.No. 3,948,264 to Wilke et al, who disclose a device for facilitatinginhalation of a powdered medication that includes a body portion havingprimary and secondary air inlet channels and an outlet channel. Thesecondary inlet channel provides an enclosure for a capsule containingthe powdered medication and the outlet channel is formed as a mouthpieceprotruding from the body. A capsule piercing structure is provided,which upon activation forms one or more holes in the capsule so thatupon vibration of the capsule by an electro-mechanical vibrator, thepowdered drug may be released from the capsule. The piercing meansdisclosed in Wilke et al includes three radially mounted, spring-biasedpiercing needles mounted in a trochoidal chamber. Upon hand rotation ofthe chamber, simultaneous inward radial motion of the needles piercesthe capsule. Further rotation of the chamber allows the needles to beretracted by their spring mountings to their original positions towithdraw the needles from the capsule. The electromechanical vibratorincludes, at its innermost end, a vibrating plunger rod which projectsinto the intersection of the inlet channel and the outlet channel.Connected to the plunger rod is a mechanical solenoid buzzer forenergizing the rod to vibrate. The buzzer is powered by a high energyelectric cell and is activated by an external button switch. Accordingto Wilke et al, upon inhalation through outlet channel 3 and concurrentpressing of switch 10 d to activate the electromechanical vibratingmeans 10, air is sucked through inlet channels 4 and 12 and the airstream through the secondary inlet channel 4 raises the capsule upagainst the vibrating plunger rod 10 a. The capsule is thus vibratedrapidly with powder being fluidized and dispensed from the pierced holestherein. (This technique is commonly used in manufacturing fordispensing powder through a hopper where the hopper is vibrated tofluidize the powder and move it through the hopper outlet. The piercedholes in the capsule represent the hopper outlet.) The air streamthrough inlet channel 4 and 12 aids in withdrawal of powder from thecapsule and carries this powder through the outlet channel 3 to themouth of the user. (Wilke et al, column 3, lines 45-55). Wilke et alfurther discloses that the electromechanical vibrator means may beplaced at a right angle to the inlet chamber and that the amplitude andfrequency of vibration may be altered to regulate dispensingcharacteristics of the inhaler.

Thus, as noted above, the vibrator in Wilke et al's disclosed inhaler isan electromechanical device consisting of a rod driven by a solenoidbuzzer. (This electromechanical means may be a motor driving a cam [Col.4, Line 40]). A disadvantage of the inhaler implementation as disclosedby Wilke is the relatively large mechanical movement required of the rodto effectively vibrate the capsule. The large movement of the rod,usually around 100s of microns, is necessary due to the elasticity ofthe capsule walls and inertia of the drug and capsule.

Moreover, solenoid buzzers typically have operating frequencies lessthan 5 Khz. This operating frequency tends to be noisy and therefore isnot desirable when incorporated into a dry powder inhaler from apatient's perspective. A further disadvantage of the electrochemicalactuators of Wilke is the requirement for a high energy source (Wilke etal, Col. 3, line 38), thus requiring a large battery source or frequentchanges of the battery pack for portable units. Both these features arenot desirable from a patient safety and “ease of use” standpoint.

The inhaler of Wilke et al is primarily intended to reduce the amount ofpowder left behind in the capsule relative to other inhalers cited inthe patent disclosure. (Wilke et al, Col. 4, lines 59-68, Col. 5, lines1-48). However, Wilke et al does not address the need to deaggregate thepowder into particle sizes or groups less than 5 microns in size as isrequired for effective delivery of the medication to the lungs; ratherWilke et al, like the prior art inhalers continues to rely on the airstream velocity to deaggregate the powder ejected into the air stream,into particle sizes suitable for delivery to the lungs.

Another prior art inhalation device is disclosed in Burns et al U.S.Pat. No. 5,284,133. In this device, a liquid medication is atomized byan ultrasonic device such as a piezo element (Burns et al, Col. 10,lines 36-51). A stream of air, usually at a high velocity, or apropellant then carries the atomized particles to the patient. Theenergy required to atomize the liquid medication in the nebulizer isprohibitively high, making this approach for the delivery of drugs tothe lungs only feasible as a desk top unit. The high voltagerequirements to drive the piezo, to produce the necessary mechanicaldisplacements, also severely affects the weight and size of the device.It is also not obvious that the nebulizer operating principles can beapplied to the dry powder inhalers for delivery or powder medication tothe lungs.

The prior art devices therefore have a number of disadvantages whichmakes them less than desirable for the delivery of dry powder to thelungs. Some of these disadvantages are:

The performance of the prior art inhalers depends on the flow rategenerated by the user. Lower flow rate does not result in the powderbeing totally deaggregated and hence adversely affects the dosedelivered to the patient.

Inconsistency in the bioavailability of the drugs from dose-to-dosebecause of lack of consistency in the deaggregation process.

Large energy requirements for driving the electromechanical basedinhalers which increases the size of the devices making them unsuitablefor portable use.

Loss of medication from opened or topped capsules.

Deterioration of medication in open or topped capsules due to exposureto oxygen or moisture.

In my prior U.S. Pat. Nos. 6,026,809 and 6,142,146 (with Abrams), weprovide an inhaler that utilizes vibration to facilitate suspension of amedication or drug into a gas that overcomes the aforesaid and otherdisadvantages and drawbacks of the above prior art. More particularly,the inhaler of our aforesaid patent includes a piezoelectric vibratorfor vibrating the medication or drug. In a preferred embodiment of ouraforesaid '809 and '146 patents, the medication or drug is supplied froma coiled tape having a plurality of spaced blisters or wells forcarrying controlled aliquots of a dry powder medication or drug.

Referring to FIG. 1 which corresponds to FIG. 9 of our aforesaid '809U.S. patent, the medication or drug is packaged in a disposable drugcartridge 210 which includes a coiled tape 218 carrying a plurality ofspaced flat walled blisters or wells 220 for containing controlledaliquots medication. A release film 221 covers and seals blisters orwells 220. Tape 218 is formed as a coil, and threaded between a firstguide platen 222 and pinch roller 224. Pinch roller 224 in turn isdriven by a take-up spool 226 which in turn is driven by a thumbwheel228 which is mounted on a common shaft with the take-up spool 226. Inuse, release film 221 is peeled from the tape 218, whereby to openblisters or wells 220, one at a time, as the film is advanced throughthe cartridge, and the release film 221 is collected on take-up spool226.

Completing cartridge 210 is a piezoelectric element 232 for mechanicallyengaging the bottom wall of the opened blisters or wells 220, one at atime, as they are selectively advanced in position over and in contactwith the piezoelectric element 232. Tape 218 also preferably includesdetent means or the like for indexing the tape so that a selected openedblister or well 220 is automatically positioned over piezoelectricelement 232. Finally, an actuating circuit and power supply (not shown)is mounted within cartridge 210.

Preferably, but not necessarily, the interior walls of the housing arecoated with a metallized coating 234 so as to obviate possibleelectrostatic charge buildup within the housing.

Also, if desired, an auxiliary air inlet 236 may be provided immediatelyupstream of the piezoelectric element 232 for assisting in carryingparticles as they are energized by the piezoelectric element.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides an improvement over the medicationpackaging and delivering technology described in our aforesaid '809 and'146 patents. More particularly, in accordance with the presentinvention, controlled aliquots or doses of a medication or drug arepre-packaged in a blister pack. The blister pack includes a frangiblecrowned top element which may be conical, conical with a rounded point,rounded, or other raised shape configuration, and a bottom element whichmay be a flat web or membrane, or which itself may be of shapedconfiguration, e.g. conical, round, dish shaped, etc. for closelyengaging with an underlying piezo element. The shape and size of theblisters is chosen to provide optimum controlled delivery of controlledamounts of controlled size particles of a given medication or drug.Before being delivered, the top element of the blister pack is piercedwith a piercing device such as a sharp needle to form one or moreapertures for delivery of the medication or drug contained within theblister pack. The hole pattern and hole size is selected to provideoptimization of delivery of the particular medication or drug packagedtherein. The holes also may act as filters whereby to prevent ejectionfrom the blisters of aggregated or agglomerated particles, until theparticles are broken up to optimal size by energy input from the piezo.Thus, in the case, e.g. of a dry powder medication or drug or a liquidmedication or drug, particle size and dose of the medication or drugdelivered can be optimized, and tailored to the frequency of the piezo.Typically, the bottom blister element is placed on/in close proximity tothe piezo prior to or contemporaneously with piercing the top element.The top element is pierced, and activation of the piezo drives themedication or drug from the blister pack through the perforations in thetop element.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the present invention will be seen fromthe following detailed description, taken in conjunction with theaccompanying drawings, wherein:

FIGS. 1 a and 1 b are schematic representations of a dry powderpackaging and delivery system in accordance with the prior art;

FIGS. 2-5 illustrate various blister packs made in accordance with thepresent invention; and

FIGS. 6A and 6B illustrate a plurality of blister packs and piezos inaccordance with another embodiment of the invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Referring to FIG. 2, a blister pack in accordance with the presentinvention comprises a bottom element 10 in the form of an elongateplastic tape or other flexible material, e.g. cloth, foil, paper, etc.,having an overlying top element 12, carrying a plurality of spaced topcrowned areas 14 containing controlled aliquots or doses of a dry powdermedication or drug or a liquid medication or drug. As illustrated inFIG. 2, the top crowned areas 14 are shaped as inverted cones and aremounted to bottom element 10 in regular spaced intervals. Areas 14 aresubstantially completely filled with a controlled aliquot or dose of apowder or liquid medication or drug. Typically, the blister pack of thepresent invention is provided as coil or a circular cartridge or unitdose pack. In use, the blister pack is uncoiled and advanced to apuncture stage where one or a plurality of controlled size holes 16 arepunched through the top wall of the top crowned area 14.

The top crown areas 14 and bottom element 10 form an enclosed volume.The shape, height and volume of the blister pack, together with the sizeand number of holes punched through the top crowned area 14, play animportant role in the de-aggregation and aerosolization of the powder orliquid material in the blister pack.

The three main phenomenon, besides others, which help in thede-aggregation and aerosolization of the material in the blister, arethe Helm-Holtz resonator, the standing waves set-up in the blister packand the vibrator frequency of the piezo. The Helm-Holtz resonator isformed by the holes punches in the top crown and the volume of theblister pack. The Helm-Holtz resonator helps to de-aggregate and ejectthe material from the blister pack. The frequency of the resonator willhave to be optimized for maximum material de-aggregation and ejectionefficiency.

The standing waves in the blister pack are determined by the height andshape of the blister. The standing waves help to lift and aerosolize thematerial in the blister. The standing wave frequency is determined bythe height and shape of the blister pack and will have to be optimizedfor maximum de-aggregation of the material in the blister.

The third main phenomenon is the piezo vibrator frequency. The piezofrequency should be such as to excite the Helm-Holtz resonator andestablish the standing waves in the blister pack. The interface of theelement 10 with the piezo vibrator should be such as to provide maximumcoupling of the piezo vibrator energy into the blister pack.

It will be appreciated by those skilled in the art that these threephenomenon need to be optimized individually or in combination toachieve maximum de-aggregation and aerosolization of the powder orliquid material in the blister pack to make it suitable for delivery ofmedication or other compounds to the lungs.

The tape is advanced so that that area 18 of the bottom portionunderlying the punctured top crowned area 14 is in contact with oradjacent the piezoelectric element 20. The piezoelectric element 20 isthen energized and couples with area 18, causing the blister pack tovibrate whereby to deaggregate and drive the powdered or liquidmedication or drug out of the blister pack through holes 16.

Other shapes of blister packs made in accordance with the invention areshown in FIGS. 3-5, and may include domed blister packs as illustratedin FIG. 3, dome/cone combinations as shown in FIG. 4, and cone/pill boxcombinations as shown in FIG. 5. In all cases the lower element shouldbe flat or nearly flat or at least have a generally flattened orslightly rounded surface for interfacing or coupling with the piezo.

A particular feature and advantage of the present invention is that theblister pack, when coupled to the piezo essentially acts as a miniaturepump which expels the powder or liquid into the air stream.

The present invention offers several other advantages over the priorart. For one, the blister pack keeps the powdered or liquid medicationsor drugs freshly sealed and dry until just prior to use. Also, theblister pack keeps the powdered or liquid medications or drugs fromflowing out or being lost, and allows the inhaler to be used in anyorientation. Additionally, the size and shape of the top and bottomblister pack elements can be tuned to specific drug/piezo combinationsfor optimizing medication or drug delivery. Also, dosage size can beadjusted simply by changing the number of blister packs opened in theair channel. In such case, the multiple blisters may be openedsimultaneously and driven by a common or by multiple piezos 20 a, 20 b .. . (see FIGS. 6A and 6B), or sequentially. Also, if desired, two ormore piezos may be employed, e.g. adjacent the bottom and sides of theblisters, and activated simultaneously or sequentially. Anotheradvantage as noted supra is that the holes in the blister pack serve asa filter or sieve so as to prevent expulsion from the blister pack ofaggregated or oversize particles. Thus, overdosing and/or waste iseliminated.

Various changes may be made in the foregoing without departing from thespirit and scope of the invention. For example, the blister pack of thepresent invention advantageously may be employed for packaging anddelivery of other wet or dry materials including, for example, vitamins,hormones, steroids and other bioactive small molecules, peptides,proteins, etc.

1. A blister pack for use with inhalation therapy inhalers equipped witha vibratory de-aggregator, comprising a first element having spacedareas for interfacing and coupling with an inhaler vibratoryde-aggregator, and a frangible second element overlying the firstelement and forming spaced top crowned areas shaped as upright conesdefining a volume located over said first element spaced areas, andcontaining powder or liquid material, wherein, upon puncture of thefrangible second element to form at least one puncture hole with an areasmaller than the spaced top crown area, the volume of the blister packand the at least one puncture hole form a standing wave or Helm-Holtzresonator whereby contents of the blister are forcibly ejected from theblister through the puncture holes in the frangible second element whenthe spaced areas are interfaced coupled with a vibratory de-aggregator.2. A blister pack according to claim 1, wherein said first elementcomprises an elongate flexible tape.
 3. A blister pack for use withinhalation therapy inhalers equipped with a vibratory de-aggregator,comprising a first element having spaced areas for interfacing andcoupling with an inhaler vibratory de-aggregator, and a frangible secondelement overlying the first element and forming spaced top crowned areasshaped as inverted domes defining a volume located over said firstelement spaced areas, and containing powder or liquid material, wherein,upon puncture of the frangible second element to form at least onepuncture hole with an area smaller than the spaced top crown area thevolume of the blister pack and the at least one puncture hole form astanding wave or Helm-Holtz resonator whereby contents of the blisterare forcibly ejected from the blister through the puncture holes in thefrangible second element when the spaced areas are interfaced coupledwith a vibratory de-aggregator.
 4. A blister pack according to claim 1,wherein the first element includes a depression opposite the top crownedareas.
 5. A blister pack according to claim 4, wherein the depression isshaped as an inverted dome.
 6. A blister pack according to claim 4,wherein the depression is shaped as an inverted pill box.
 7. A blisterpack according to claim 1, wherein said material comprises a medication.8. A blister pack according to claim 1, wherein said material comprisesa vitamin.
 9. A blister pack according to claim 1, wherein said materialcomprises a hormone.
 10. A blister pack according to claim 1, whereinsaid material comprises a steroid.
 11. A blister pack according to claim1, wherein said material comprises a bioactive material.
 12. A blisterpack according to claim 1, wherein a size and number of puncture holestogether with volume formed by the blister pack are optimized forde-aggregation and aerosolization of material in the blister pack.
 13. Ablister pack according to claim 1, wherein a height and shape of theblister pack is optimized for de-aggregation and aerosolization ofmaterial in the blister pack.
 14. A blister pack according to claim 1,wherein an interface to the vibrator is optimized for optimum couplingof the energy into the blister pack for de-aggregation andaerosolization of material in the blister pack.